The Baylor-Hopkins Clinical Genomics Center (BHCGC), incorporating the Baylor College of Medicine (BCM) Human Genome Sequencing Center (HGSC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR) will perform at least 900,000 whole genome array genotype assays and 700,000 whole genome sequences with a minimum of 35-fold coverage, over five years, for the National Institutes of Health?s All of Us Program (AoU). The work will all be carried out in CAP/CLIA certified environments and will favor Illumina platforms, with a projected average cost of less than $31 per genotype and $647 per WGS, respectively. Sequencing and analyses will be performed with NIH compliant pipelines and population-aware methods applied for phasing and ancestry determination. Automated methods will identify and rank putative pathogenic or likely pathogenic variants for every participant, and make available the results in both ?pre-reports? and in a searchable environment, assisting selection of a subset of individuals for Clinical Validation. Signed, Clinical Reports will be generated for up to six thousand participants per year, leveraging BCM?s deep experience in genetic interpretation. The partnership will maintain a secure cloud Baylor-Hopkins AoU Portal (BHAoU Portal) to manage sample tracking and to distribute all data, with symmetric access to BHCGC and AoU DCR and GRC members. Data flow and population level analyses will be overseen by partners at the University of Texas School of Public Health (UTSPH), DNAnexus will facilitate the cloud-based data communication and a collaboration with Microsoft Research will innovate in optimized computing. A new ?Frontiers of Interpretation? group will work locally, and with Microsoft, for application of AI methods for variant interpretation. Approximately 300 genomes will be ?upgraded? in quality with a battery of with other sequencing methods, in the first year, to determine the impact on Clinical Reporting and guide program adjustments. Pursuit of innovation for enhanced analytical value or cost efficiencies will be a priority. Direct deliverables to the AoU DRC will include sample metadata, raw and processed genomic data, variant interpretations, and preliminary and signed Clinical Reports. In addition, all protocols, tools, and software developed for the All of Us program will be made available to the program and to the broader scientific community.